1245. In Vivo Efficacy of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) Against β-Lactamase-Producing (BLP) Gram-Negative Bacteria in a Neutropenic Murine Pneumonia Model

Abstract

BackgroundCarbapenems are often used for Extended-Spectrum β-lactamase (ESBL)- and cephalosporinase (AmpC or CMY)-producing infections. Their increased use resulted in the emergence of carbapenem resistance among Gram-negatives, promoting the need of an effective carbapenem-sparing option. WCK 4282 (FEP 2g-TZB 2g) maximizes systemic exposure of TZB and restores FEP activity against piperacillin-tazobactam (TZP) resistant isolates in vitro. Herein we describe the efficacy of WCK 4282 clinical exposures against BLP Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in a murine pneumonia model.MethodsClinical isolates (14 EB and 2 PA) with in vitro resistance to FEP, ceftolozane-tazobactam, and TZP (EB isolates) were used. Isolates expressed ESBLs, AmpC/CMY, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-16 and 8-32 mg/L for non-carbapenemase and carbapenemase-producers, respectively. Human-simulated regimens (HSR) of FEP (mimicking human plasma exposure of 2g q8h as a 1.5 h infusion) alone and in combination with TZB (equivalent to 2g q8h as a 1.5 h infusion) were developed in a neutropenic pneumonia model. Treatment mice received FEP or FEP-TZB (WCK 4282) HSR. Control mice were vehicle-dosed. Efficacy was assessed as change in log10CFU/lung at 24 h compared with 0 h controls.ResultsMean 0 h bacterial density across all isolates was 6.66 ± 0.29 log10CFU/lung and increased at 24 h by 2.48 ± 0.6 and 1.71 ± 1.13 among controls and FEP-treated groups, respectively. Potent WCK 4282 activity was observed against ESBL- and AmpC-harboring EB as well as ESBL- and AmpC-overexpressing PA with WCK 4282 MICs up to 16 mg/L (n=9); mean bacterial reductions were -2.70 ± 0.63 and -2.04 ± 0.18 log10CFU/lung, respectively. WCK 4282 showed variable activity against OXA-48-producing EB (n=3); log10CFU/lung change ranged from -1.2 to 0.28. Against KPC-producers (n=4), WCK 4282 groups grew to 0.53 ± 1.07 log10CFU/lung, ~1.2 log10CFU lower than FEP.ConclusionWCK 4282 produced potent in vivo activity against ESBL- and AmpC-harboring Gram-negative isolates and limited activity among serine carbapenamase-producers in a pneumonia model at clinically achievable exposures. Further studies are warranted to delineate WCK 4282’s spectrum of activity and susceptibility breakpoint.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)